WO2012062870A1 - Phosphoramidates de nucléoside d'uracyle spirooxétane - Google Patents

Phosphoramidates de nucléoside d'uracyle spirooxétane Download PDF

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Publication number
WO2012062870A1
WO2012062870A1 PCT/EP2011/069865 EP2011069865W WO2012062870A1 WO 2012062870 A1 WO2012062870 A1 WO 2012062870A1 EP 2011069865 W EP2011069865 W EP 2011069865W WO 2012062870 A1 WO2012062870 A1 WO 2012062870A1
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WO
WIPO (PCT)
Prior art keywords
hcv
compound
added
mixture
mmol
Prior art date
Application number
PCT/EP2011/069865
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English (en)
Inventor
Tim Hugo Maria Jonckers
Pierre Jean-Marie Bernard Raboisson
Koen Vandyck
Steven Maurice Paula Van Hoof
Lili Hu
Abdellah Tahri
Original Assignee
Janssen Products, Lp
Medivir Ab
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Janssen Products, Lp, Medivir Ab filed Critical Janssen Products, Lp
Priority to US13/884,852 priority Critical patent/US9012428B2/en
Priority to EP11785634.4A priority patent/EP2638054B1/fr
Priority to DK11785634.4T priority patent/DK2638054T3/en
Priority to PL11785634T priority patent/PL2638054T3/pl
Priority to ES11785634.4T priority patent/ES2531583T3/es
Publication of WO2012062870A1 publication Critical patent/WO2012062870A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals
    • C07H19/10—Pyrimidine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2068—Compounds of unknown constitution, e.g. material from plants or animals

Definitions

  • This invention relates to an uracyl spirooxetane nucleoside phosphoramidate useful in the treatment of patients infected with the hepatitis C virus (HCV).
  • HCV hepatitis C virus
  • HCV is a single stranded, positive-sense RNA virus belonging to the Flaviviridae family of viruses in the hepacivirus genus.
  • the NS5B region of the RNA polygene encodes a RNA dependent RNA polymerase (RdRp), which is essential to viral replication.
  • RdRp RNA dependent RNA polymerase
  • HCV hepatocellular carcinoma
  • HCV HCV
  • Transmission of HCV can occur through contact with contaminated blood or blood products, for example following blood transfusion or intravenous drug use.
  • the introduction of diagnostic tests used in blood screening has led to a downward trend in post-transfusion HCV incidence.
  • the existing infections will continue to present a serious medical and economic burden for decades.
  • HCV therapy is based on (pegylated) interferon-alpha (IFN-a) in combination with ribavirin.
  • IFN-a interferon-alpha
  • This combination therapy yields a sustained virologic response in more than 40% of patients infected by genotype 1 HCV and about 80% of those infected by genotypes 2 and 3.
  • this combination therapy has significant side effects and is poorly tolerated in many patients.
  • Major side effects include influenza-like symptoms, hematologic
  • concentration for the respective drugs in an HIV regime frequently falls below the IC 90 or ED 90 threshold for large parts of the day. It is considered that a 24 hour trough level of at least the IC 50 , and more realistically, the IC 90 or ED 90 , is essential to slow down the development of drug escape mutants.
  • the NS5B RdRp is essential for replication of the single- stranded, positive sense, HCV RNA genome. This enzyme has elicited significant interest among medicinal chemists. Both nucleoside and non-nucleoside inhibitors of NS5B are known. Nucleoside inhibitors can act as a chain terminator or as a competitive inhibitor, or as both. In order to be active, nucleoside inhibitors have to be taken up by the cell and converted in vivo to a triphosphate. This conversion to the triphosphate is commonly mediated by cellular kinases, which imparts additional structural requirements on a potential nucleoside polymerase inhibitor. In addition this limits the direct evaluation of nucleosides as inhibitors of HCV replication to cell-based assays capable of in situ phosphorylation.
  • nucleosides as inhibitors of HCV RdRp, none have proceeded all the way to registration.
  • problems which HCV- targeted nucleosides have encountered to date are toxicity, mutagenicity, lack of selectivity, poor efficacy, poor bioavailability, sub-optimal dosage regimes and ensuing high pill burden, and cost of goods.
  • HCV inhibitors that may overcome the disadvantages of current HCV therapy such as side effects, limited efficacy, the emerging of resistance, and compliance failures, as well as improve the sustained viral response.
  • Spirooxetane nucleosides in particular l-(2-O,2-C-ethano-P-D-ribofuranosyl)thymine and l-(2-O,2-C-ethano- P-D-ribofuranosyl)uracil have been described in Org. Biomol. Chem., 2003, 3514- 3526. These compounds were tested against HIV, but no activity was found.
  • the compound of the invention may also be attractive due to the fact that it lacks activity against other viruses, in particular against HIV. HIV-infected patients often suffer from co-infections such as HCV. Treatment of such patients with an HCV inhibitor that also inhibits HIV may lead to the emergence of resistant HIV strains.
  • the present invention provides for butyl N-[(S)- ⁇ [(4R,5R,7R,8R)-5-(2,4- dioxo-3,4-dihydropyrimidin-l(2H)-yl)-8-hydroxy-l,6-dioxaspiro[3.4]oct-7-yl] methoxy ⁇ (phenoxy)phosphoryl]-L-alaninate and the pharmaceutically acceptable salts and solvates thereof.
  • This compound is represented by the formula I:
  • the invention concerns the use of the compound of formula I as a medicine, more in particular, for inhibiting HCV.
  • the present invention concerns a compound of formula I for use in the treatment or prophylaxis of HCV infection.
  • a compound of formula I for the manufacture of a medicament for inhibiting HCV is provided.
  • the present invention concerns the use of a compound of formula I for the manufacture of a medicament for the treatment or prophylaxis of HCV infection.
  • HCV genotypes in the context of treatment or prophylaxis in accordance with the invention include genotype lb (prevalent in Europe) or la (prevalent in North America).
  • the invention also provides a method for the treatment or prophylaxis of HCV infection, in particular of the genotype la or lb.
  • the compound of formula (I) is a pure stereoisomeric form.
  • a pure stereoisomeric form as mentioned herein is defined as a stereoisomer substantially free of other enantiomeric or diastereomeric forms of the same basic molecular structure of the compound of formula (I).
  • a pure stereoisomeric form concerns a compound having a stereoisomeric excess of at least 80% (i.e. minimum 90% of one isomer and maximum 10% of the other possible isomers) up to a stereoisomeric excess of 100%) (i.e.
  • unit dosage forms are tablets (including scored or coated tablets), capsules, pills, suppositories, powder packets, wafers, injectable solutions or suspensions and the like, and segregated multiples thereof.
  • an antiviral effective daily amount would be from about 1 to about 200 mg/kg, or about 5 to about 175 mg/kg, or about 10 to about 150 mg/kg, or about 20 to about 100 mg/kg, or about 50 to about 75 mg/kg body weight. Average daily doses can be obtained by multiplying these daily amounts by about 70. It may be appropriate to administer the required dose as two, three, four or more sub-doses at appropriate intervals throughout the day. Said sub-doses may be formulated as unit dosage forms, for example, containing about 1 to about 5000 mg, or about 50 to about 3000 mg, or about 100 to about 1000 mg, or about 200 to about 600 mg, or about 100 to about 400 mg of active ingredient per unit dosage form.
  • the term “about” has the meaning known to the person skilled in the art. In certain embodiments the term “about” may be left out and the exact amount is meant. In other embodiments the term “about” means that the numerical following the term “about” is in the range of ⁇ 15%, or of ⁇ 10%, or of ⁇ 5%, or of ⁇ 1%, of said numerical value.
  • reaction product 5 was purified by silica gel chromatography (600 g silica), by gradient elution with 15% to 20% ethyl acetate in hexane to give the reaction product 5 as a colorless oil (32.9 g, 70%).
  • reaction mixture was then stirred with 1 N HC1 and extracted with dichloromethane.
  • the organic layers were combined and washed with saturated aqueous NaHC0 3 followed by brine.
  • MgS0 4 filtration and evaporation of the volatiles, the residue was purified by column chromatography (400 g silica) eluting with heptane to 15% ethyl acetate in heptane to give reaction product as an oil (as a mixture with compound 5).
  • the mixture was purified again with CH 2 CI 2 as eluent (400 g silica).
  • the pure fractions were collected and intermediate 6 was obtained as a colorless oil (13.05 g, 39 %).
  • Example 3 Synthesis of intermediate l-[(2R,3R,4R,5R)-3-allyl-4-(benzyloxy)-5- (benzyloxymethyl)-3-hydroxytetrahydrofuran-2-yl]pyrimidine-2,4(lH,3H)-dione (7) i3 ⁇ 4 ' s(trimethylsilyl)acetamide (BSA; 29.2 mL, 118 mmol) was added to a mixture of 6 (14.0 g, 23.1 mmol) and uracil (5.99 g, 53.4 mmol) in anhydrous acetonitrile (300 mL). The reaction mixture was refluxed for 1 hour and the clear solution was allowed to cool down to room temperature.
  • BSA trimethylsilyl)acetamide
  • Tinchloride (11.55 mL, 99 mmol) was added dropwise at room temperature and the mixture was further stirred for 1 hour. The mixture was then stirred at reflux for 1.5 hour and again cooled to room temperature. Ethyl acetate (250 mL) was added, followed by saturated aqueous NaHCC"3 (250 mL) and the mixture was stirred for 15 minutes. After filtration through Celite, the organic layer was separated and washed with saturated aqueous NaHC03 (250 mL). The combined aqueous layer was extracted with ethyl acetate (250 mL) and the combined organic layer was dried (MgS0 4 ), filtered and evaporated to dryness under reduced pressure.
  • the combined aqueous layer was extracted with ethyl acetate and the combined organic layer was dried over (Na 2 S0 4 ), filtered and evaporated to dryness under reduced pressure.
  • the oily residue obtained was dissolved in a mixture of THF (100 mL) and H 2 0 (20 mL) and sodium borohydride (1.361 g, 36.0 mmol) was added. The reaction mixture was stirred overnight at room temperature, whereupon water (100 mL) was added and extraction was performed with ethyl acetate (2x50 mL).
  • reaction product 8 was purified by column chromatography (0-10% (v/v) methanol in CH 2 C1 2 then 10%> isocratic) affording reaction product 8 as a white foam (4.8 g, 57 %).
  • HPLC Condition A, Rt: 2.12 min, m/z 469 (M+H) + .
  • Methanesulfonyl chloride (0.800 mL, 10.34 mmol) was added to 8 (4.32 g, 9.22 mmol) in dry pyridine (100 mL). After 1 hour and 15 minutes, 0.1 equivalents more methanesulfonyl chloride was added and the mixture was further stirred at room temperature for 45 minutes. Then, a small amount of methanol was added and the mixture was evaporated to dryness. The residue was dissolved in ethyl acetate (100 mL) and washed with saturated NaHC0 3 (2x50 mL). The combined aqueous layer was extracted with ethyl acetate. The combined organic layer was then dried over Na 2 S0 4 and
  • the compound PI was examined for activity in the inhibition of HCV-RNA replication in a cellular assay.
  • the assay was used to demonstrate that compound PI inhibited a HCV functional cellular replicating cell line, also known as HCV replicons.
  • the cellular assay was based on a bicistronic expression construct, as described by
  • This cell line harbors an RNA encoding a bicistronic expression construct comprising the wild type NS3-NS5B regions of HCV type lb translated from an internal ribosome entry site (IRES) from encephalomyocarditis virus (EMCV), preceded by a reporter portion (FfL-luciferase), and a selectable marker portion (neo R , neomycine phosphotransferase).
  • IRS internal ribosome entry site
  • EMCV encephalomyocarditis virus
  • FfL-luciferase reporter portion
  • neo R neomycine phosphotransferase
  • the replicon cells were plated in 384-well plates in the presence of the test and control compounds which were added in various concentrations. Following an incubation of three days, HCV replication was measured by assaying luciferase activity (using standard luciferase assay substrates and reagents and a Perkin Elmer ViewLuxTM ultraHTS microplate imager). Replicon cells in the control cultures have high luciferase expression in the absence of any inhibitor. The inhibitory activity of the compound on luciferase activity was monitored on the Huh-Luc cells, enabling a dose-response curve for the test compound. The EC 50 value was then calculated, which value represents the amount of the compound required to decrease the level of detected luciferase activity by 50%, or more specifically, the ability of the genetically linked HCV replicon RNA to replicate. The result is shown in table 1.
  • Active ingredient as used throughout this example relates to a compound of formula (I), including a pharmaceutically acceptable salt thereof or a solvate thereof.
  • a mixture of 100 g of active ingredient, 570 g lactose and 200 g starch is mixed well and thereafter humidified with a solution of 5 g sodium dodecyl sulphate and 10 g polyvinylpyrrolidone in about 200 ml of water.
  • the wet powder mixture is sieved, dried and sieved again.
  • 100 g microcrystalline cellulose and 15 g hydrogenated vegetable oil is added. The whole is mixed well and compressed into tablets, giving 10.000 tablets, each comprising 10 mg of active ingredient.
  • the tablet cores are coated with the thus obtained mixture in a coating apparatus.

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Abstract

Cette invention concerne un phosphoramidate de nucléoside d'uracyle spirooxétane stéréochimiquement pur utile dans le traitement de patients infectés avec le virus de l'hépatite C (HCV).
PCT/EP2011/069865 2010-11-10 2011-11-10 Phosphoramidates de nucléoside d'uracyle spirooxétane WO2012062870A1 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
US13/884,852 US9012428B2 (en) 2010-11-10 2011-11-10 Uracyl spirooxetane nucleoside phosphoramidates
EP11785634.4A EP2638054B1 (fr) 2010-11-10 2011-11-10 Phosphoramidates de nucléoside d'uracyle spirooxétane
DK11785634.4T DK2638054T3 (en) 2010-11-10 2011-11-10 URACYLSPIROOXETANNUCLEOSIDE PHOSPHORAMIDATES
PL11785634T PL2638054T3 (pl) 2010-11-10 2011-11-10 Fosforoamidany nukleozydów uracylo-spirooksetanowych
ES11785634.4T ES2531583T3 (es) 2010-11-10 2011-11-10 Fosforamidatos de espironucleósido oxetánico uracílico

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP10190660.0 2010-11-10
EP10190660 2010-11-10

Publications (1)

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WO2012062870A1 true WO2012062870A1 (fr) 2012-05-18

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US (1) US9012428B2 (fr)
EP (1) EP2638054B1 (fr)
DK (1) DK2638054T3 (fr)
ES (1) ES2531583T3 (fr)
PL (1) PL2638054T3 (fr)
PT (1) PT2638054E (fr)
WO (1) WO2012062870A1 (fr)

Cited By (8)

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US8507460B2 (en) 2011-10-14 2013-08-13 Idenix Pharmaceuticals, Inc. Substituted 3′,5′-cyclic phosphates of purine nucleotide compounds and pharmaceutical compositions for the treatment of viral infections
WO2014008236A1 (fr) * 2012-07-03 2014-01-09 Bristol-Myers Squibb Company Procédé de préparation de dérivés de phosphoramidates enrichis en diastéréo-isomères de composés de nucléosides, destinés au traitement d'infections virales
WO2014033617A1 (fr) * 2012-08-31 2014-03-06 Novartis Ag Dérivés de 2'-éthynyle nucléoside de traitement d'infections virales
US9109001B2 (en) 2012-05-22 2015-08-18 Idenix Pharmaceuticals, Inc. 3′,5′-cyclic phosphoramidate prodrugs for HCV infection
US9296778B2 (en) 2012-05-22 2016-03-29 Idenix Pharmaceuticals, Inc. 3′,5′-cyclic phosphate prodrugs for HCV infection
US9403863B2 (en) 2011-09-12 2016-08-02 Idenix Pharmaceuticals Llc Substituted carbonyloxymethylphosphoramidate compounds and pharmaceutical compositions for the treatment of viral infections
US9422323B2 (en) 2012-05-25 2016-08-23 Janssen Sciences Ireland Uc Uracyl spirooxetane nucleosides
WO2021209427A1 (fr) * 2020-04-14 2021-10-21 Janssen Sciences Ireland Unlimited Company Analogues nucléosidiques spirocycliques pour le traitement de l'hépatite e

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AU2013266393B2 (en) 2012-05-22 2017-09-28 Idenix Pharmaceuticals Llc D-amino acid compounds for liver disease
WO2014052638A1 (fr) 2012-09-27 2014-04-03 Idenix Pharmaceuticals, Inc. Esters et malonates de promédicaments à base de s-acyl-2-thioéthyle (sate)
ES2674980T3 (es) 2012-10-08 2018-07-05 Idenix Pharmaceuticals Llc Análogos de 2'-cloro nucleósidos para infección por VHC
US10723754B2 (en) 2012-10-22 2020-07-28 Idenix Pharmaceuticals Llc 2′,4′-bridged nucleosides for HCV infection
EP2935304A1 (fr) 2012-12-19 2015-10-28 IDENIX Pharmaceuticals, Inc. 4'-fluoro-nucléosides pour le traitement du vhc
US9309275B2 (en) 2013-03-04 2016-04-12 Idenix Pharmaceuticals Llc 3′-deoxy nucleosides for the treatment of HCV
US9339541B2 (en) 2013-03-04 2016-05-17 Merck Sharp & Dohme Corp. Thiophosphate nucleosides for the treatment of HCV
EP2970357A1 (fr) 2013-03-13 2016-01-20 IDENIX Pharmaceuticals, Inc. Pronucléotides de phosphoramidate d'acide aminé de 2'-cyano, azido et amino nucléosides pour le traitement du virus de l'hépatite c (vhc)
WO2014165542A1 (fr) 2013-04-01 2014-10-09 Idenix Pharmaceuticals, Inc. 2',4'-fluoronucléosides pour le traitement du vhc
US10005779B2 (en) 2013-06-05 2018-06-26 Idenix Pharmaceuticals Llc 1′,4′-thio nucleosides for the treatment of HCV
EP3027636B1 (fr) 2013-08-01 2022-01-05 Idenix Pharmaceuticals LLC Phosphoramidate de d-acides aminés pronucleotidiques dérivés de pyrimidine halogenée pour des maladies du foie
WO2015161137A1 (fr) 2014-04-16 2015-10-22 Idenix Pharmaceuticals, Inc. Nucléosides méthyle ou alcynyle substitués en position 3 pour le traitement du virus de l'hépatite c
UA124966C2 (uk) 2015-03-06 2021-12-22 Атеа Фармасеутікалс, Інк. <font face="Symbol">b</font>-D-2'-ДЕЗОКСИ-2'-<font face="Symbol">a</font>-ФТОР-2'-<font face="Symbol">b</font>-C-ЗАМІЩЕНІ-2-МОДИФІКОВАНІ-N<sup>6</sup>-ЗАМІЩЕНІ ПУРИНОВІ НУКЛЕОТИДИ ДЛЯ ЛІКУВАННЯ ВИКЛИКАНИХ HCV ЗАХВОРЮВАНЬ
LU100724B1 (en) 2016-07-14 2018-07-31 Atea Pharmaceuticals Inc Beta-d-2'-deoxy-2'-alpha-fluoro-2'-beta-c-substituted-4'-fluoro-n6-substituted-6-amino-2-substituted purine nucleotides for the treatment of hepatitis c virus infection
EP3865136A1 (fr) 2016-09-07 2021-08-18 ATEA Pharmaceuticals, Inc. Nucléotides de purine substitués en position 2'-n 6 pour le traitement du virus corona
KR20230151050A (ko) 2017-02-01 2023-10-31 아테아 파마슈티컬즈, 인크. C형 간염 바이러스를 치료하기 위한 뉴클레오티드 헤미-술페이트 염
TW202012001A (zh) 2018-04-10 2020-04-01 美商亞堤製藥公司 C型肝炎病毒(hcv)感染硬化之患者的治療
US10874687B1 (en) 2020-02-27 2020-12-29 Atea Pharmaceuticals, Inc. Highly active compounds against COVID-19

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Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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US8507460B2 (en) 2011-10-14 2013-08-13 Idenix Pharmaceuticals, Inc. Substituted 3′,5′-cyclic phosphates of purine nucleotide compounds and pharmaceutical compositions for the treatment of viral infections
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PT2638054E (pt) 2015-03-02
ES2531583T3 (es) 2015-03-17
US20130244968A1 (en) 2013-09-19
PL2638054T3 (pl) 2015-05-29
DK2638054T3 (en) 2015-03-09
US9012428B2 (en) 2015-04-21
EP2638054B1 (fr) 2014-12-03

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